This invention relates to a pharmaceutical composition. In particular, it relates to an improved liquid pharmaceutical composition suitable for the treatment of epilepsy. It further relates to a liquid pharmaceutical composition suitable for use as an anaesthetic.
Midazolam, i.e. 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4] is a diazepine of the formula:

Is a well-documented product with sedative, anxiolytic, amnesic and hypnotic properties. It is commercially available in the form of its hydrochloride, for example in the form of a glycerine-based syrup sold under the trade name VERSED®, which contains 2.5 mg/ml of midazolam. It is also sold in the form of its maleate salt, for example in tablets containing 7.5 mg or 15 mg per tablet under the trade mark DORMICUM®. A product which is formulated for administration via the buccal route is EPISTATUS®. Buccal formulations of midazolam are also disclosed in EP1323422.
It is known that midazolam can exist in solution both in a closed ring form and also in an open ring form. These two forms are in equilibrium with one another:

The amount of the open ring form (Ia) present in aqueous solution is influenced by pH. A chart showing the effect of pH on the proportion of midazolam present in the open ring form is provided as FIG. 1.
One of the factors determining the rate of physiological absorbtion of midazolam is the proportion of open ring (Ia) midazolam present in the formulation. The closed ring form (I) of midazolam is lipophilic and is more rapidly absorbed than the open ring form (Ia). It is therefore desirable to provide a formulation in which the majority of midazolam is present in the closed ring form (I).
While attempts to develop therapeutically effective higher pH formulations of midazolam have been made, these have been unsuccessful due to the inverse relationship between pH and the solubility of midazolam. For example, Olivier et al, International Journal of Pharmaceutics, 2001 (213), pages 187 to 192, concluded the satisfactory solubilisation of midazolam at higher pHs was a problem that remained to be solved.
At pH 8, the solubility of midazolam is just 0.055 mg/ml in aqueous solution. To deliver a therapeutically effective amount of such a solution, the volume required would be unacceptably large.
WO01/30391 provides an example of an attempt to formulate midazolam at a higher pH while circumventing the problem of reduced solubility. This is achieved by the use of cyclodextrin, which forms an inclusion complex with midazolam, retaining it in solution. However, the release of midazolam from cyclodextrin complexes is slow and this increases the time lag between administration and the onset of therapeutic effect.
As a result of the low solubility of midazolam at higher pHs, commercially available liquid formulations of midazolam tend to have pHs of no greater than about 5 as at these pHs, there is a sufficiently high proportion of midazolam in the closed ring form to ensure an acceptable degree of efficacy, while the solubility of midazolam is sufficient to enable a relatively low volume of carrier liquid to be used.
For example, in a typical syrup for oral administration, e.g. VERSED® syrup, the pH ranges from 2.8 to 3.6. Within that range, the solution may contain up to about 40% of midazolam in the open ring form (Ia). Following administration, the medicament will become exposed to physiologic conditions, including pHs in the range of 5 to 8, and will be absorbed into systemic circulation under those conditions. Thus, the majority of the midazolam present in the open-ring form present in the medicament will be converted to the closed ring form upon absorbtion. However, this change of pH and absorbance of midazolam will not occur immediately, upon administration, and there is a time lag between administration and the onset of therapeutic activity of approximately 10 to 30 minutes.
The buccally administered form of midazolam, EPISTATUS® is an extremely convenient and straightforward vehicle for delivering midazolam rapidly to patients suffering from epileptic seizures or significant amounts of pain. The pH of the EPISTATUS® product is around 4.5 to 5.5 and the proportion of midazolam in the open ring form (Ia) is approximately 1%.
The rate of absorbtion of midazolam from the EPISTATUS® formulation is sufficiently high to provide a rapid onset of therapeutic effect in patients. However, in view of the importance of the rapid delivery of midazolam to patients in need thereof, it would nevertheless be advantageous if the rate of absorbtion could be improved.
This is because epileptic seizures are a common cause of neurological medical emergency and may result in brain damage. Failure to relieve the symptoms of an epileptic seizure in less than about 15 minutes may lead to death. Accordingly, it is extremely desirable to treat a patient suffering from an epileptic seizure as promptly as possible so as to minimise the risk of brain damage or death to the patient. Additionally, when used as an anaesthetic, it is desirable, for obvious reasons, to treat a patient suffering from pain as promptly as possible.
The use of injectable formulations of midazolam is common. While midazolam administered in this way will have a rapid onset of therapeutic effect, it will not be suitable for use in all patient groups. For example, the use of a needled syringe with a patient suffering from an epileptic seizure will be problematic and potentially dangerous to both the patient and the healthcare professional administering the medicament. Additionally, the use of needled syringes is likely to raise anxiety in certain patient groups, such as children.
Accordingly, the administration of midazolam via the mucous membranes of a patient is a desirable route of administration for midazolam. Administration via this route offers the advantages of rapid therapeutic onset as well as the avoidance of needled syringes. Administration of midazolam via the buccal, nasal, rectal and/or sub-lingual mucous membranes is especially desirable.
Attempts to prepare formulations of midazolam for nasal administration have been made, for example, as reported by Wilton et al., Anesthesiology 1988, 69, pages 972-5. Most studies on intranasal formulations of midazolam have made use of a dilute aqueous midazolam injection solution that is not suitable for nasal administration because of a low pH (3 or less) which causes intense discomfort to patients and also because they are prone to nasal run-off.
Attempts have been made to overcome these problems. For example, Wermeling et al., Anasthesia & Analgesia, August 2006, volume 103 number 2, pages 344-349, developed a formulation containing midazolam, polyethylene glycol 400, butylated hydroxytoluene, saccharin and propylene glycol. That formulation provided 2.5 mg of midazolam in a 0.1 mL spray delivered using a modified version of a commercially available unit-dose spray pump. However, the formulation was associated with numerous adverse events, including eye watering (58% of doses), dizziness (17% of doses), bad taste (25% of doses), and nasal congestion/feeling nasopharyngeal irritation (100% of doses).
There is accordingly a need to provide an improved formulation for the administration of midazolam to the mucosal membranes of a patient in need thereof, e.g. a patient suffering an epileptic seizure, or suffering from unacceptable levels of pain.